The Design And Synthesis Of Compounds Derived From Antitumor AKBA Via Structure Modification

Nowadays,cancer has become a serious threat to the lives of people in China.It has become one of the major diseases leading to death.The incidence and mortality rate of cancer are still increasing,and cancer is a problem for the whole world.Therefore,to develop an anticancer drug is a very difficult task.Boswellic acid AKBA is a triterpenoid isolated from Boswellia serrata.It was found that structure modification of AKBA usually focused on derivation of the two functional groups in A ring,thus a large number of derivatives were prepared through formation of ester bond,amide linkage and other way.In the present work,47 derivatives were prepared by means of ring expansion;ring cleavaging,ring contraction and introducing functional groups.They were 24-substituted-urs-12-en-3,11-dione-3,4-lactones(or lactam);3,4-seco-24-de-methyl-urs-12-en-4,11-dione-3-oates(or amide);Polyol and its derivatives;A-nor-l-substituted-24-hydroxy(or acetoxy or propionyloxy)-urs-1(3),12-dien-11-ones.Their structures were characteriz ed by analysis of 1H-NMR,13C-NMR and MS data.The cytotoxic activities against four cancer cell lines(human prostate cancer cells PC-3,human lung adenocarcinoma cells A549,human chronic myeloid leukemia K562 and human primary myeloid leukemia cells HL-60)and a human normal cell line(human bronchial epithelial cells HBE)of the synthesized 47 compounds were determined using MTT colorimetric method,with AKBA and doxorubicin as control.The screening results showed that the introdution of a cyano group into the derived structure did not improve cytotoxic activity obviously.After A-ring was expanded to a seven membered lactam ring,the derived compounds exerted obvious cytotoxic activity selectively against K562.When the hydroxyl group of the structure was esterified,the activity was further improved,but the selectivity reduced,the compound had better cytotoxicity against the other three tumor cells.The cytotoxic activity of those compounds with cleavaged A rings was similar to that of to AKBA.Compounds Ⅱ4-Ⅱ9,derivatives of compound Ⅱ0 by acylation,showed higher cytotoxicity than AKBA,among which compound Ⅱ6 showed most potent anti-tumor activity with IC50 values were 6.07,4.20,8.28 and 8.62μM for K562,HL60,PC-3 and A549,respectively.However,the IC50 values of the compounds with another nitrogen atom in the substituent group were at the range of 2.10～8.66μM.Their cytotoxic activity was increased by 3～8 fold compared with AKBA,indicating that the nitrogen atoms contribute to the enhancement of the anti-tumor activity.The polyhydroxyl derivatives of AKBA had cytotoxic activity.Their activities were not significantly improved by acylation of the hydroxyl groups at C-2,C-3 and C-4 and the change of spatial configuration in A ring.Among the obtained compounds,Ⅲa0,Ⅲc1 and Ⅲe1 had good selectivity to PC3,and the IC50 values were 6.93 μM,5.71 μM and 7.15μM,respectively.Ⅲb0,Ⅲdl and Ⅲd2 had selectivity to HL60 to some extent,and the IC50 values were 8.56μM,6.85μM and 8.43μM,respectively,which was better than AKBA.Compounds IV1-IV5 derived from contraction of A ring did not improved the cytotoxic activity significantly compared with AKBA at a concentration of 25μM Nevertheless,the cytotoxic activity of compounds Ⅳ6-Ⅳ10 against cancer cell lines increased,but the cytotoxicity against normal cell line increased too.The cytotoxic mechanism of active compounds Ⅱ11 and Ⅳ10 were initially explored using flow cytometry with fluorescein Annexin V-FITC/PI staining.Th e results showed that they could incuce necrosis in HL-60 cell.